Direct-Ink-Writing 3D-Printed Bioelectronics.

The development of wearable and implantable bioelectronics has garnered significant momentum in recent years, driven by the ever-increasing demand for personalized health monitoring, remote patient management, and real-time physiological data collection. The elevated sophistication and advancement of these devices have thus led to the use of many new and unconventional materials which cannot be fulfilled through traditional manufacturing techniques. Three-dimension (3D) printing, also known as additive manufacturing, is an emerging technology that opens new opportunities to fabricate next-generation bioelectronic devices. Some significant advantages include its capacity for material versatility and design freedom, rapid prototyping, and manufacturing efficiency with enhanced capabilities. This review provides an overview of the recent advances in 3D printing of bioelectronics, particularly direct ink writing (DIW), encompassing the methodologies, materials, and applications that have emerged in this rapidly evolving field. This review showcases the broad range of bioelectronic devices fabricated through 3D printing including wearable biophysical sensors, biochemical sensors, electrophysiological sensors, energy devices, multimodal systems, implantable devices, and soft robots. This review will also discuss the advantages, existing challenges, and outlook of applying DIW 3D printing for the development of bioelectronic devices toward healthcare applications.

Cage Environment Regulates Gut Microbiota Independent of Toll-Like Receptors.

The gut microbiome orchestrates epithelial homeostasis and both local and remote immunological responses. Critical to these regulatory interactions are innate immune receptors termed Toll-like receptors (TLRs). Studies to date have implicated innate immunity and Toll-like receptors in shaping key features of the gut microbiome. However, a variety of biological and environmental variables are also implicated in determining gut microbiota composition. In this report, we hypothesized that cohousing and environment dominated the regulation of the gut microbiota in animal models independent of innate immunity. To determine the importance of these variables, innate immunity, or environment in shaping gut microbiota, we used a randomized cohousing strategy and transgenic TLR-deficient mice. We have found that mice cohoused together by genotype exhibited limited changes over time in the composition of the gut microbiota. However, for mice randomized to cage, we report extensive changes in the gut microbiota, independent of TLR function, whereby the fecal microbiota of TLR-deficient mice converges with that of wild-type mice. TLR5-deficient mice in these experiments exhibit greater susceptibility to comparative changes in the microbiota than other TLR-deficient mice and wild-type mice. Our work has broad implications for the study of innate immunity and host-microbiota interactions. Given the profound impact that gut dysbiosis may have on immunity, this report highlights the potential impact of cohousing on the gut microbiota and indices of inflammation as outcomes in biological models of infectious or inflammatory disease.

Decision-making by the NICE Interventional Procedures Advisory Committee.

BACKGROUND: This study explored the evidence base for recommendations by the National Institute of Health and Care Excellence (NICE) Interventional Procedures Advisory Committee, the only NICE committee not to consider cost. The four potential recommendations are: Standard Arrangements (can be performed as routine practice in the NHS); Special Arrangements (can be done under certain conditions); Research Only; and Do Not Do. METHODS: Quantitative content analysis of data extracted from all published Interventional Procedure Guidance (IPG) for 2003-2018 (n = 496) was undertaken. All data were extracted independently by two researchers; disagreements were clarified by consensus. Data were tabulated, descriptive statistics produced, and regression analyses performed. RESULTS: The proportion of IPGs by recommendation was: 50·0 per cent Standard Arrangements; 37·2 per cent Special Arrangements; 11·1 per cent Research Only; and 1·6 per cent Do Not Do. There was a clear trend over time: the proportion of recommendations for Standard Arrangements decreased, whereas the evidence threshold increased. Adjusted mean numbers of patients in the evidence base by recommendation type were: Standard, 4867; Special, 709; Research Only, 386. Regression analyses confirmed that the year of recommendation, numbers of patients and levels of evidence all affected the likely recommendation. CONCLUSION: This study suggests that the likelihood of achieving the most positive recommendation (Standard Arrangements) is decreasing, and that this is most likely due to evidential requirements becoming more demanding. These findings are distinct from those reported for other NICE committees, for which the cost and statistical superiority of new therapies are among the drivers of recommendations.

ANTECEDENTES: Este estudio analiza los niveles de evidencia de las recomendaciones propuestas por el Interventional Procedures Advisory Committee del National Institute of Health and Care Excellence (NICE), el único comité NICE que no tiene en consideración los costes en la guía para los procedimientos de intervención. Las cuatro recomendaciones potenciales son: disposiciones estándar (se pueden efectuar sin restricciones en el marco del NHS); disposiciones especiales (se pueden efectuar bajo ciertas condiciones), en el ámbito de la investigación solo; y no intervenir. MÉTODOS: Se realizó un análisis cuantitativo del contenido de todas las Interventional Procedure Guidance (IPG) publicadas entre 2003-2018 (n = 496). Se obtuvieron todos los datos de forma independiente por dos investigadores y los desacuerdos entre ellos se decidieron por consenso. Se tabularon los datos y se realizaron estadísticas descriptivas y análisis de regresión. RESULTADOS: La proporción de las IPG según el tipo de recomendación eran estándar en el 50% de los casos, especial en el 37%, solo investigación en el 11% y no intervenir en el 2%. Se observó una clara tendencia a lo largo del tiempo: la proporción de recomendaciones del tipo de disposiciones estándar disminuía, mientras que el umbral para la evidencia aumentaba. La media ajustada del número de pacientes para cada tipo de recomendación (estándar, específica y solo investigación) fue de 4.867, 709 y 386, respectivamente. Los análisis de regresión confirmaron que el año de la recomendación, el número de pacientes y los niveles de evidencia afectaban el tipo de recomendación. Estos resultados son diferentes a los relativos a otros comités de NICE, en los que el coste y la superioridad estadística de las nuevas terapias son los motores de las recomendaciones. CONCLUSIÓN: Este estudio sugiere que la probabilidad de lograr la recomendación más positiva (disposición estándar) está disminuyendo, y ello con toda probabilidad es debido a que los requerimientos relacionados con la evidencia son cada vez más exigentes.

Human leucocyte antigen-adverse drug reaction associations: from a perspective of ethnicity.

Whilst immune-mediated adverse drug reactions (ADRs) are rare, they are potentially life-threatening and present a major problem for clinicians. The underlying mechanisms that cause ADRs are not fully understood although genomewide association studies (GWAS) and case-control investigations have associated human leucocyte antigen (HLA) alleles as risk factors. There is evidence that a patient's ethnic background can have an impact on their risk of developing an ADR. This review summarizes the evidence related to HLA alleles and ADRs with particular focus on patient ethnicity. Our analysis indicated that many of the alleles which have been associated with ADRs are found at higher frequencies in Asian populations. The data also showed that many of the alleles that are reported to be statistically significantly associated with ADRs are in linkage disequilibrium with each other and that they form haplotypes specific to certain ethnicities indicating at least some of the allele associations may not be causal.

Standards of care in cauda equina syndrome.

What constitutes cauda equina syndrome (CES), how it should be subclassified and how urgently to image and operate on patients with CES are all matters of debate. A structured review of the literature has led us to evaluate the science and to propose evidence-based guidelines for the management of CES. Our conclusions include this guidance: pain only; MRI negative - recommend: analgesia, ensure imaging complete (not just lumbar spine) adequate follow-up. Bilateral radiculopathy (CESS) with a large central disc prolapse - recommend: discuss with the patient and if for surgery, the next day (unless deteriorates to CESI in which case emergency surgery); CESI - recommend: the true emergency for surgery by day or night; a large central PLID with uncertainty as to whether CESI or CESR (e.g. catheterised prior to CESR) or where there is residual cauda equina nerve root function or early CESR - recommend: treat as an emergency by day or night. Where there has been prolonged CESR and/or no residual sacral nerve root function - recommend: treat on the following day's list.

Exploring the influence of trust relationships on motivation in the health sector: a systematic review.

BACKGROUND: Dedicated and motivated health workers (HWs) play a major role in delivering efficient and effective health services that improve patients' experience of health care. Growing interest in HW motivation has led to a global focus on pay for performance strategies, but less attention has been paid to nurturing intrinsic motivation. Workplace trust relationships involve fair treatment and respectful interactions between individuals. Such relationships enable cooperation among HWs and their colleagues, supervisors, managers and patients and may act as a source of intrinsic motivation. This paper presents findings from a qualitative systematic review of empirical studies providing evidence on HW motivation, to consider what these studies suggest about the possible influence of workplace trust relationships over motivation. METHODS: Five electronic databases were searched for articles reporting research findings about HW motivation for various cadres published in the 10-year period 2003 to 2013 and with available full free text in the English language. Data extraction involved consideration of the links between trust relationships and motivation, by identifying how studies directly or indirectly mention and discuss relevant factors. RESULTS: Twenty-three articles from low- and middle-income countries and eight from high-income countries that met predetermined quality and inclusion criteria were appraised and subjected to thematic synthesis. Workplace trust relationships with colleagues, supervisors and managers, employing organisation and patients directly and indirectly influence HW motivation. Motivational factors identified as linked to trust include respect; recognition, appreciation and rewards; supervision; teamwork; management support; autonomy; communication, feedback and openness; and staff shortages and resource inadequacy. CONCLUSION: To the authors' knowledge, this is the first systematic review on trust and motivation in the health sector. Evidence indicates that workplace trust relationships encourage social interactions and cooperation among HWs, have impact on the intrinsic motivation of HWs and have consequences for retention, performance and quality of care. Human resource management and organisational practices are critical in sustaining workplace trust and HW motivation. Research and assessment of the levels of motivation and factors that encourage workplace trust relationships should include how trust and motivation interact and operate for retention, performance and quality of care.

Assessing variation in the costs of care among patients awaiting liver transplantation.

Previous economic analyses of liver transplantation have focused on the cost of the transplant and subsequent care. Accurate characterization of the pretransplant costs, indexed to severity of illness, is needed to assess the economic burden of liver disease. A novel data set linking Medicare claims with transplant registry data for 15,710 liver transplant recipients was used to determine average monthly waitlist spending (N = 249,434 waitlist months) using multivariable linear regression models to adjust for recipient characteristics including Model for End-Stage Liver Disease (MELD) score. Characteristics associated with higher spending included older age, female gender, hepatocellular carcinoma, diabetes, hypertension and increasing MELD score (p < 0.05 for all). Spending increased exponentially with severity of illness: expected monthly spending at a MELD score of 30 was 10 times higher than at MELD of 20 ($22,685 vs. $2030). Monthly spending within MELD strata also varied geographically. For candidates with a MELD score of 35, spending varied from $19,548 (region 10) to $36,099 (region 7). Regional variation in waitlist costs may reflect the impact of longer waiting times on greater pretransplant hospitalization rates among high MELD score patients. Reducing the number of high MELD waitlist patients through improved medical management and novel organ allocation systems could decrease total spending for end-stage liver care.

Community-based distribution of misoprostol to prevent postpartum haemorrhage at home births: results from operations research in rural Ghana.

OBJECTIVE: To report on a rigorous distribution and monitoring plan to track misoprostol for community-based distribution to reduce postpartum haemorrhage (PPH) in rural Ghana. DESIGN: Operations research. SETTING: Rural Ghana. SAMPLE: Women in third trimester of pregnancy presenting to primary health centres (PHCs) for antenatal care (ANC). METHODS: Ghana Health Service (GHS), Millennium Village Projects, and the University of Illinois at Chicago conducted an operations research study designed to assess the safety, feasibility, and acceptability of community-based distribution of misoprostol to prevent PPH at home deliveries in rural Ghana. One thousand doses (3000 tablets, 200 µg each) were obtained from the Family Health Division of GHS. Three 200-µg tablets of misoprostol (600 µg) in foil packets were packaged together in secured transparent plastic packets labelled with pictorial messages and distributed to midwives at seven PHCs for distribution to pregnant women. MAIN OUTCOME MEASURES: Correct use of misoprostol in home deliveries and retrieval of unused misoprostol doses, PPH rates and maternal mortality. RESULTS: Of the 999 doses distributed to midwives, 982 (98.3%) were successfully tracked, with a 1.7% lost to follow-up rate. Midwives distributed 654 doses to women at third-trimester ANC visits. Of women who had misoprostol to use at home, 81% had an institutional delivery and were able to return the misoprostol safely to the midwife. Of the women that used misoprostol, 99% used the misoprostol correctly. CONCLUSIONS: This study clearly demonstrates that misoprostol distributed antenatally to pregnant women can be used accurately and reliably by rural Ghanaian women, and should be considered for policy implementation across Ghana and other countries with high home birth rates and maternal mortality ratios.

Multimodal Soft Robotic Actuation and Locomotion.

Diverse and adaptable modes of complex motion observed at different scales in living creatures are challenging to reproduce in robotic systems. Achieving dexterous movement in conventional robots can be difficult due to the many limitations of applying rigid materials. Robots based on soft materials are inherently deformable, compliant, adaptable, and adjustable, making soft robotics conducive to creating machines with complicated actuation and motion gaits. This review examines the mechanisms and modalities of actuation deformation in materials that respond to various stimuli. Then, strategies based on composite materials are considered to build toward actuators that combine multiple actuation modes for sophisticated movements. Examples across literature illustrate the development of soft actuators as free-moving, entirely soft-bodied robots with multiple locomotion gaits via careful manipulation of external stimuli. The review further highlights how the application of soft functional materials into robots with rigid components further enhances their locomotive abilities. Finally, taking advantage of the shape-morphing properties of soft materials, reconfigurable soft robots have shown the capacity for adaptive gaits that enable transition across environments with different locomotive modes for optimal efficiency. Overall, soft materials enable varied multimodal motion in actuators and robots, positioning soft robotics to make real-world applications for intricate and challenging tasks.

Multicolour spectral karyotyping of mouse chromosomes.

Murine models of human carcinogenesis are exceedingly valuable tools to understand genetic mechanisms of neoplastic growth. The identification of recurrent chromosomal rearrangements by cytogenetic techniques serves as an initial screening test for tumour specific aberrations. In murine models of human carcinogenesis, however, karyotype analysis is technically demanding because mouse chromosomes are acrocentric and of similar size. Fluorescence in situ hybridization (FISH) with mouse chromosome specific painting probes can complement conventional banding analysis. Although sensitive and specific, FISH analyses are restricted to the visualization of only a few mouse chromosomes at a time. Here we apply a novel imaging technique that we developed recently for the visualization of human chromosomes to the simultaneous discernment of all mouse chromosomes. The approach is based on spectral imaging to measure chromosome-specific spectra after FISH with differentially labelled mouse chromosome painting probes. Utilizing a combination of Fourier spectroscopy, CCD-imaging and conventional optical microscopy, spectral imaging allows simultaneous measurement of the fluorescence emission spectrum at all sample points. A spectrum-based classification algorithm has been adapted to karyotype mouse chromosomes. We have applied spectral karyotyping (SKY) to chemically induced plasmocytomas, mammary gland tumours from transgenic mice overexpressing the c-myc oncogene and thymomas from mice deficient for the ataxia telangiectasia (Atm) gene. Results from these analyses demonstrate the potential of SKY to identify complex chromosomal aberrations in mouse models of human carcinogenesis.

Anisotropic Ion Conducting Particulate Composites for Bioelectronics.

Acquisition, processing, and manipulation of biological signals require transistor circuits capable of ion to electron conversion. However, use of this class of transistors in integrated sensors or circuits is limited due to difficulty in patterning biocompatible electrolytes for independent operation of transistors. It is hypothesized that it would be possible to eliminate the need for electrolyte patterning by enabling directional ion conduction as a property of the material serving as electrolyte. Here, the anisotropic ion conductor (AIC) is developed as a soft, biocompatible composite material comprised of ion-conducting particles and an insulating polymer. AIC displays strongly anisotropic ion conduction with vertical conduction comparable to isotropic electrolytes over extended time periods. AIC allows effective hydration of conducting polymers to establish volumetric capacitance, which is critical for the operation of electrochemical transistors. AIC enables dense patterning of transistors with minimal leakage using simple solution-based deposition techniques. Lastly, AIC can be utilized as a dry, anisotropic interface with human skin that is capable of non-invasive acquisition of individual motor action potentials. The properties of AIC position it to enable implementation of a wide range of large-scale organic bioelectronics and enhance their translation to human health applications.

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses.

There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and meta-analyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.

Tensor correlations measured in 3He(e,e' pp)n.

We have measured the 3He(e,e' pp)n reaction at an incident energy of 4.7 GeV over a wide kinematic range. We identified spectator correlated pp and pn nucleon pairs by using kinematic cuts and measured their relative and total momentum distributions. This is the first measurement of the ratio of pp to pn pairs as a function of pair total momentum p(tot). For pair relative momenta between 0.3 and 0.5 GeV/c, the ratio is very small at low p(tot) and rises to approximately 0.5 at large p(tot). This shows the dominance of tensor over central correlations at this relative momentum.

Measurement of single- and double-spin asymmetries in deep inelastic pion electroproduction with a longitudinally polarized target.

We report the first measurement of the transverse momentum dependence of double-spin asymmetries in semi-inclusive production of pions in deep-inelastic scattering off the longitudinally polarized proton. Data have been obtained using a polarized electron beam of 5.7 GeV with the CLAS detector at the Jefferson Lab (JLab). Modulations of single spin asymmetries over the azimuthal angle between lepton scattering and hadron production planes ϕ have been measured over a wide kinematic range in Bjorken x and virtual photon squared four-momentum Q2. A significant nonzero sin2ϕ single spin asymmetry was observed for the first time indicating strong spin-orbit correlations for transversely polarized quarks in the longitudinally polarized proton.

Absorption of the ω and ϕ mesons in nuclei.

Because of their long lifetimes, the ω and ϕ mesons are the ideal candidates for the study of possible modifications of the in-medium meson-nucleon interaction through their absorption inside the nucleus. During the E01-112 experiment at the Thomas Jefferson National Accelerator Facility, the mesons were photoproduced from 2H, C, Ti, Fe, and Pb targets. This Letter reports the first measurement of the ratio of nuclear transparencies for the e+e- channel. The ratios indicate larger in-medium widths compared with what have been reported in other reaction channels. The absorption of the ω meson is stronger than that reported by the CBELSA-TAPS experiment and cannot be explained by recent theoretical models.

Colorectal and anal neoplasms following liver transplantation.

OBJECTIVE: Liver transplantation (LT) is the treatment of choice for end-stage liver disease. The required immunosuppression increases the risk for developing malignancies. Some viruses play a crucial role. Data on neoplasms of the colon, rectum and anus in LT are limited. METHOD: A retrospective evaluation of the incidence and clinical course of colorectal and anal malignancies and colonic polyps in a series of 467 consecutive LTs in 402 individuals between 1998 and 2001 was performed. Standard immunosuppression included Tacrolimus, Mycophenolic acid and steroids. RESULTS: During a median follow up of 5.2 years, three colon adenocarcinomas, one EBV associated cecal posttransplant lymphoproliferative tumour and two HPV associated anal tumours were identified. Pre-LT colonoscopy was performed in 161 patients (40%), and of 153 evaluable individuals, 53 (34.9%) had polyps. Colonoscopy was performed in 186 patients (46.3%) median 14.8 (range 0.2-77.8) months post-LT and 55 (29.3%) had polyps. Post-LT adenomatous polyps were detected in 47.3% of patients with pre-LT polyps vs 6.7% of patients without pre-LT polyps (P < 0.001). Patients with alcoholic liver disease had a significantly higher rate of adenoma formation (50.0% vs 11.1%, P < 0.001). No patient died from colorectal/anal malignancy. CONCLUSION: The incidence of metachronous and new polyp formation in our study is similar to people who are not immunocompromised, but subgroups are at increased risk. Viral-associated malignancies, including post-transplant lymphoproliferative disorders and anal cancer, are important entities in the LT population suggesting that complete screening of the colon, rectum and anus including pre-LT and post-LT colonoscopy should be utilized.

Best supportive care in lung cancer trials is inadequately described: a systematic review.

The objective of the paper was to identify and discuss clinical terms associated with the availability and delivery of best supportive care for patients with lung cancer in randomised controlled clinical trials. Systematic review was carried out of relevant studies without language restrictions identified through Medline, EMBASE, Science Citation Index (Web of Science and ISI Proceedings) and Cochrane Library. Reference lists of retrieved articles were also searched to identify further studies. Articles describing randomised controlled trials or systematic reviews with a comparator arm of best supportive care for patients with lung cancer were studied. Definitions of best supportive care and elements of best supportive care were reported. Included clinical studies (n = 40) did not adequately describe or outline either the components or the delivery of best supportive care for patients in lung cancer trials. None of the identified studies provided a clear definition of a patient pathway in relation to best supportive care, or a clear list of components. Clinical studies are being conducted without a clear definition of the best supportive care provided in the comparator arms of trials. Inadequate definitions mean that all direct and indirect comparisons in trials comparing active treatments with best supportive care must be interpreted with caution.

alpha 2-macroglobulin adsorbed to colloidal gold: a new probe in the study of receptor-mediated endocytosis.

alpha 2-Macroglobulin (alpha 2 M) was adsorbed to colloidal gold and used as a new tool in the study of receptor-mediated endocytosis. alpha 2 M-gold is easy to prepare and is clearly visualized at the electron microscope level. When cells were incubated with alpha 2 M-gold at 0 degrees C, gold was visualized both diffusely over the cell surface and concentrated in coated pits. After cells to which alpha 2 M-gold had been bound at 0 degrees C were warmed, the gold was rapidly internalized into uncoated vesicles, previously termed receptosomes. After 30 min of incubation or longer, gold was found in small lysosomes and, later, in large lysosomes and very small vesicles in the region of the Golgi complex. This pattern of localization is similar to that previously described, using peroxidase-labeled anti-alpha 2 M antibodies. By incubating cells with both alpha 2 M-gold and vesicular stomatitis virus (VSV), we studied the internalization of these two markers simultaneously. VSV and alpha 2 M-gold rapidly clustered in the same coated pits and were internalized in the same receptosomes. Proteins and hormones adsorbed to gold may be useful in the study of receptor-mediated endocytosis.

Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth.

The hormone 17 beta-estradiol acts through its receptor system to induce MCF-7 human breast cancer cells to form tumors in athymic mice. In vitro studies have identified the production of estrogen-induced growth factors from MCF-7 cells that may have a role in growth control. These induced growth factors were sufficient to stimulate MCF-7 tumor growth in ovariectomized athymic mice, thus partially replacing estradiol. Growth factors may act as estrogen-induced "second messengers" in estrogen-responsive growth of human breast cancer.

Ultraviolet light: a new stimulus for the induction of platelet aggregation.

Exposure to ultraviolet light (253.7 nanometers) causes mammalian blood platelets to aggregate. Aggregation is markedly enhanced in the presence of extracellular fibrinogen and is followed by the grodual of relatively small amounts of nucleotide and serotonin. Aggregation is inhibited by ethylenediamine tetraacetic acid or a combination of 2-deoxy-D-glucose and antimycin A. Adenosine, apyrase, and prostaglandin E(1) produced slight inhibition. The effect of exposure to ultraviolet light is cumulative and lasting. This agent may be used to study the process of platelet aggregation after the removal of the stimulus, by delaying the addition of fibrinogen until after cessation of irradiation. Thus ultraviolet light is the first agent known which may be used to study platelet aggregation in a period following its removal.